This Mentored Career Development Award seeks to combine a program of focused research, individualized mentorship and didactics to provide the candidate with the training in advanced genomics and longitudinal study design. The applicant has already completed psychiatry residency training and PhD centered around single variant genetic association studies involving cross-sectional data. His career goal is to become an independent investigator, conducting studies that further our understanding of the genetic and environmental factors underlying major depression in a manner that improves the lives of individuals suffering from this disorder. The applicant proposes to build on his background and develop a new set of skills necessary to achieve this career goal. The focused research part in the award will build on epidemiological studies that indicate that genes and life stress are two of the most important factors in the etiology of depression. Over the past decade, there has been growing interest in identifying interactions between specific genes and stress in the development of depression. Despite the excitement surrounding the initial studies, our ability to draw definitive conclusions is compromised by significant study design limitations: 1) substantial variation in the character and intensity of stress between subjects 2) retrospective design 3) loss of power due to tests of statistical interaction. Unfortunately, because the onset of chronic stress is so difficult to predict beforehand and because the type of stress encountered varies widely between individuals, designing methods to overcome these limitations has been difficult. Medical internship, the first year of professional physician training, presents a unique situation where the onset of a uniform, chronic stressor can be prospectively predicted. The first research aim of this study is: to identify longitudinal trajectories of depressive symptoms among medical interns after the onset of internship stress. This will allow the candidate to achieve the first training aim of the study: to develop a strong foundation in longitudinal design and analytic techniques. The second research aim of this study is: to evaluate the interaction between genetic variation (single nucleotide polymorphisms and copy number variants) in depression candidate pathways and internship stress on both the level and trajectory of depressive symptoms under the stress of internship. This will allow the candidate to achieve the second training aim of the study: to develop expertise in advanced genomic tools. PUBLIC HEALTH RELEVANCE: Major depression affects approximately 1 in 6 Americans at some point in their lives. According to the World Health Organization, depression will soon be second only to heart disease in terms of disease-associated disability. Unfortunately, depression treatments that are currently available are only partially effective. This project is designed to help uncover new biological pathways that can be targeted to develop more effective and more precise anti-depressant treatments.